Imaging Dopamine D2 Agonist Binding Sites in Cocaine Dependence with [11C]NPA

使用 [11C]NPA 对可卡因依赖中的多巴胺 D2 激动剂结合位点进行成像

• 批准号: 7587737
• 负责人: RAJESH NARENDRAN
• 金额: $ 18.94万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-15 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7587737
• 关键词: Acute; Affinity; Agonist; Amphetamines; Animals; Annual Reports; Binding; Binding Sites; Brain; Chronic; Clinical; Clinical Investigator; Clinical Research; Cocaine; Cocaine Abuse; Cocaine Dependence; Competitive Binding; Complex; Corpus striatum structure; Coupled; Crack Cocaine; Cues; Data; Dependence; Dopamine; Dopamine Agonists; Dopamine D2 Receptor; Drug Exposure; Drug usage; Evaluation; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; GTP-Binding Proteins; Goals; Health; Human; Image; Influentials; Kinetics; Life; Ligands; Link; Literature; Measurement; Measures; Methods; Microdialysis; Nature; Neurons; Nucleus Accumbens; Patients; Peripheral; Pharmaceutical Preparations; Plague; Population; Positron-Emission Tomography; Process; Property; Public Health; Raclopride; Relapse; Relative (related person); Reporting; Reproducibility; Role; Site; Stress; Surveys; Synapses; Techniques; Testing; Ventral Striatum; addiction; cocaine exposure; cocaine use; craving; design; drug of abuse; extracellular; human subject; imaging modality; in vivo; postsynaptic; pre-clinical; preclinical study; presynaptic; psychostimulant; public health relevance; radioligand; radiotracer; receptor; response; reuptake; single photon emission computed tomography; transmission process; uptake

DESCRIPTION (provided by applicant): The sensitization response is an increased striatal dopaminergic response to a psychostimulant challenge that occurs in animals after repeated and prolonged exposure to a drug of abuse such as cocaine or amphetamine (Kalivas and Stewart, 1991; Robinson and Berridge, 1993; Vezina, 2004). This exaggerated DA response measured with microdialysis techniques is a well-validated and established phenomenon in the preclinical addiction literature. In sharp contrast to the chronic cocaine animals, three studies in cocaine dependent human subjects (CDS) have now reported a severe blunting (decrease) in the stimulant induced reduction in [11C]raclopride and [123I]IBZM in the striatum (and ventral striatum that includes the accumbens) (Malison et al., 1999; Martinez et al., 2006; Volkow et al., 1997). If one were to assume the decrease in [11C]raclopride binding following a stimulant challenge is purely reflective of presynaptic DA release, the results of the clinical imaging studies in humans suggesting a decreased dopaminergic tone (blunting) would be inconsistent with the preclinical studies in animals showing an increased dopaminergic tone (sensitization) following chronic and repeated exposure to cocaine. Nevertheless the smaller displacement of the antagonists [123I]IBZM or [11C]raclopride following stimulant challenge in CDS might result from a smaller increase in synaptic dopamine concentration following stimulants (i.e. presynaptic factors) or from decreased D2 receptor affinity for DA (i.e. postsynaptic factors), or from some combination of both factors. Available imaging methods do not allow to tease apart the respective contributions of these factors, because of the lack of radioligands to measure D2 agonist binding interactions. Despite the fact that D2 antagonist radioligands such as [123I]IBZM and [11C]raclopride have contributed tremendously to our understanding of dopamine transmission, they have been plagued by their relatively low sensitivity and ceiling effect (following stimulant challenges) which are presumably related to the fact that D2 antagonist bind to both high (D2high) and low (D2low) affinity states (Laruelle, 2000). The endogenous agonist dopamine is expected to compete efficiently with a D2 agonist radioligand such as [11C]NPA that binds preferentially to the agonist high affinity state than with an antagonist ligands such as [11C]raclopride that fails to distinguish between affinity states. Furthermore [11C]NPA is expected to have a smaller in vivo Bmax than [11C]raclopride for it binds to only a sub population of the binding of the antagonist radioligand (D2high and D2low). In this application we present evidence supporting both these hypotheses (Narendran et al., 2005; Narendran et al., 2004). This application proposes to further develop and characterize this radiotracer in healthy human subjects (test/retest reliability) and perform an exploratory study probing the role for decreased D2 agonist binding sites in cocaine dependence. PUBLIC HEALTH RELEVANCE: The overall goal of this application is to develop and validate a method that will make it possible to characterize the pre- or post-synaptic nature of the dysregulation of dopamine transmission revealed by the amphetamine challenge in patients with cocaine dependence.

描述（由申请方提供）：致敏反应是动物在重复和长期暴露于滥用药物（如可卡因或苯丙胺）后对精神兴奋剂激发的纹状体多巴胺能反应增加（Kalivas和Stewart，1991;罗宾逊和Berridge，1993; Vezina，2004）。用微透析技术测量的这种夸大的DA反应是临床前成瘾文献中得到充分验证和确立的现象。与慢性可卡因动物形成鲜明对比的是，在可卡因依赖性人类受试者（CDS）中的三项研究现在已经报道了纹状体（和包括纹状体的腹侧纹状体）中刺激物诱导的[11 C]雷氯必利和[123 I]IBZM减少的严重钝化（减少）（Malison等人，1999; Martinez等人，2006年; Volkow等人，1997年）。如果假设刺激激发后[11 C]雷氯必利结合减少纯粹反映突触前DA释放，则表明多巴胺能张力降低（钝化）的人体临床成像研究结果与表明长期重复暴露于可卡因后多巴胺能张力增加（致敏）的动物临床前研究结果不一致。然而，在CDS中，在刺激物激发后，拮抗剂[123 I]IBZM或[11 C]雷氯必利的较小位移可能是由于刺激物（即突触前因子）后突触多巴胺浓度的较小增加或D2受体对DA的亲和力降低（即突触后因子），或两种因素的某种组合。可用的成像方法不允许梳理除了这些因素的各自的贡献，因为缺乏放射性配体来测量D2激动剂结合相互作用。尽管D2拮抗剂放射性配体如[123 I]IBZM和[11 C]雷氯必利对我们理解多巴胺传递做出了巨大贡献，但它们一直受到其相对较低的敏感性和天花板效应（在刺激物激发后）的困扰，这可能与D2拮抗剂结合高（D2高）和低（D2低）亲和力状态的事实有关（Laruelle，2000）。预期内源性激动剂多巴胺与D2激动剂放射性配体如[11 C]NPA有效竞争，所述放射性配体优先结合激动剂高亲和力状态，而不是与拮抗剂配体如[11 C]雷氯必利有效竞争，所述拮抗剂配体不能区分亲和力状态。此外，预期[11 C]NPA的体内Bmax小于[11 C]雷氯必利，因为其仅结合拮抗剂放射性配体的结合亚群（D2高和D2低）。在本申请中，我们提出了支持这两种假设的证据（Narendran等人，2005; Narendran等人，2004年）。本申请提出在健康人类受试者中进一步开发和表征这种放射性示踪剂（测试/再测试可靠性），并进行探索性研究，探索D2激动剂结合位点减少在可卡因依赖中的作用。公共卫生相关性：本申请的总体目标是开发和验证一种方法，该方法将使其能够表征可卡因依赖患者中安非他明激发所揭示的多巴胺传递失调的突触前或突触后性质。